title: Functional Integration of the Conserved Domains of Shoc2 Scaffold.
abstract: Shoc2 is a positive regulator of signaling to extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Shoc2 is also proposed to interact with RAS and Raf-1 in order to accelerate ERK1/2 activity. To understand the mechanisms by which Shoc2 regulates ERK1/2 activation by the epidermal growth factor receptor (EGFR), we dissected the role of Shoc2 structural domains in binding to its signaling partners and its role in regulating ERK1/2 activity. Shoc2 is comprised of two main domains: the 21 leucine rich repeats (LRRs) core and the N-terminal non-LRR domain. We demonstrated that the N-terminal domain mediates Shoc2 binding to both M-Ras and Raf-1, while the C-terminal part of Shoc2 contains a late endosomal targeting motif. We found that M-Ras binding to Shoc2 is independent of its GTPase activity. While overexpression of Shoc2 did not change kinetics of ERK1/2 activity, both the N-terminal and the LRR-core domain were able to rescue ERK1/2 activity in cells depleted of Shoc2, suggesting that these Shoc2 domains are involved in modulating ERK1/2 activity.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Myoungkun
authors.initials: M
authors.lastname: Jeoung
authors.forename: Lina
authors.initials: L
authors.lastname: Abdelmoti
authors.forename: Eun Ryoung
authors.initials: ER
authors.lastname: Jang
authors.forename: Craig W
authors.initials: CW
authors.lastname: Vander Kooi
authors.forename: Emilia
authors.initials: E
authors.lastname: Galperin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D004815:Epidermal Growth Factor / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C112913:SHOC2 protein, human; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020559:Monomeric GTP-Binding Proteins